Compositions and methods of treating chronic pain by administering propofol derivatives
a technology of propofol derivatives and compositions, applied in the direction of drug compositions, hydroxy compound active ingredients, antipyretics, etc., can solve the problems of limiting the utility of gabaa-r as an analgesic, and achieve the effects of enhancing gabaa-r activity, limiting its utility as analgesic, and pronounced sensitivity
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example 1
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[0143]General chemicals used in electrophysiology were of the highest purity from Sigma Aldrich (St. Louis, Mo.) as was 2,4-di-tert-butylphenol (2,4-DTBP) (137731), 2,6-di-tert-butylphenol (2,6-DTBP) (D48400) and DHβCD (H107).
[0144]For in vitro electrophysiological experiments, Propofol (TCI America, Portland, Oreg.), 2,6-DTBP, 2,6-Di-sec-butylphenol (ACROS 152830050—obtained via Fisher Scientific), 2,4-DTBP, and 2,4-Di-sec-butylphenol (S367907, Sigma Rare Chemicals Library) were normally dissolved in DMSO at 500 mM, and then diluted in the recording solution prior to use. In some experiments, 2,6-DTBP was dissolved in 40% 2-hydroxypropyl-beta-cyclodextrin at 1% (48.5 mM) and was diluted before use in recording solution to confirm that the 2-hydroxypropyl-beta-cyclodextrin solubilized compound (as used in animal experiments) had an equivalent efficacy to the DMSO solubilized material.
[0145]2-hydroxypropyl-beta-cyclodextrin was obtained from Sigma (H107-5G and C-0...
example 2
at Therapeutically Acceptable Concentrations, Powerfully and Selectively Antagonizes the Function of HCN1 Channels
[0181]The principal effects of propofol on wild type (wt) HCN1 are recapitulated in FIGS. 2A-2D. Inspection of the TEVC current families and the corresponding tail currents obtained in the absence and presence of 20 μM propofol showed that the drug slows opening, accelerates closing and shifts gating to more hyperpolarized potentials. A fit of the Hill equation to the results from a number of such experiments shows the apparent affinity (EC50 about 7-13 μM) and maximal efficacy (ΔV1 / 2 of −35 to −45 mV) of the propofol-mediated hyperpolarization of gating (see also Cacheaux et al., 2005).
[0182]As previously reported, the slower and more cAMP sensitive HCN2 and HCN4 channels were, respectively, weakly and almost completely insensitive to the anesthetic.
[0183]With reference to FIGS. 4A-4E, the experiments showed that subanesthetic propofol alleviates at least two modalities...
example 3
ic Doses of Propofol Reduce Mechanical Allodynia and Mechanical and Thermal Hyperalgesia
[0184]FIG. 12A shows PW IPSI and PW CONTRA in post-PNL mice as a function of stimulus strength (Von Frey fibers ranging from 0.6 to 4 g) and i.p. propofol administration (cumulative dose of propofol ranging from 0 to 60 mg / kg). These doses of propofol markedly reduced the mechanical hyperalgesia observed in the ipsilateral paw with only modest disturbance of normal mechanical nociceptive response as monitored in the contralateral paw. PW IPSI was significantly higher than PW CONTRA in the absence of propofol, but the difference was significantly reduced upon administration of 20 mg / kg propofol and, at a dose of 60 mg / kg, the response becomes indistinguishable from the control value of PW CONTRA. In contrast, 20 to 60 mg / kg propofol had no statistically significant effect on PW CONTRA suggesting that in the absence of neuropathy, mechanical nociceptive reflexes are relatively insensitive to propof...
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